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Role of Human Apolipoprotein E in Hepatitis B Virus Infection and Morphogenesis

人载脂蛋白 E 在乙型肝炎病毒感染和形态发生中的作用

基本信息

批准号：
10267767
负责人：
GUANGXIANG George LUO
金额：
$ 42.04万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-22 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10267767
关键词：
Affect Antibodies Antiviral Agents Antiviral Therapy Apolipoprotein E Binding Biological Assay Biology Cell Culture System Cell Culture Techniques Cell Line Cessation of life Chronic Chronic Hepatitis Chronic Hepatitis B Circular DNA Cirrhosis Clinical Co-Immunoprecipitations Cysteine DNA Viruses Data Development Electron Microscopy Family Family member Fibrosis Genes Genome Glucosamine Glypican Goals Hepadnaviridae Heparan Sulfate Proteoglycan Heparin Hepatitis B Hepatitis B Vaccines Hepatitis B Virus Hepatocyte Human Immunologics Individual Infection Infectious hepatitides Interferons Knock-out Knowledge LDL-Receptor Related Protein 1 Liver diseases Low Density Lipoprotein Receptor Mediating Mediation Molecular Molecular Target Monoclonal Antibodies Morphogenesis Mus Mutagenesis Outcome Patients Phosphorylation Physiological Play Primary carcinoma of the liver cells Production Proteins Public Health Risk Role Small Interfering RNA Surface Testing Therapeutic United States Vaccines Viral hepatitis Virion Virus Virus Diseases Virus Replication World Health Organization base chronic liver disease drug development drug discovery env Gene Products global health glycosylation in vivo inhibitor/antagonist knock-down novel nucleoside analog prevent proteoglycan core protein prototype receptor receptor binding virus envelope virus host interaction

项目摘要

Summary Hepatitis B virus (HBV) is a common cause of human liver diseases, including chronic hepatitis, steatosis, fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). HBV chronically infects more than 250 million people worldwide, including 1.25 million in the United States. Although HBV vaccine has greatly contributed to the reduction of new cases of HBV infection and HCC, it does not offer therapeutic benefits to the hundreds of millions of chronic HBV carriers. The World Health Organization has called for the elimination of viral hepatitis as a public health threat by the year 2030. The biggest challenge to curing chronic hepatitis B is the elimination of HBV covalently closed circular DNA (cccDNA), which is the molecular basis for persistent HBV replication. Existing antiviral therapies with interferon and/or nucleoside analogs can effectively suppress HBV replication but do not significantly affect the level of HBV cccDNA. Thus, there is an urgent need to discover and develop new classes of antiviral drugs capable of eliminating chronic HBV infection. In this regard, a more thorough understanding of HBV infection, replication, and morphogenesis holds a great promise to identify novel targets for antiviral drug discovery and development. Through preliminary studies, we have discovered that human apolipoprotein E (apoE) is associated with infectious HBV. More importantly, our preliminary data suggest that apoE plays critical roles in both HBV infection and morphogenesis. ApoE-specific antibodies could efficiently neutralize HBV infectivity. Also, knockdown of apoE expression or knockout of apoE gene resulted in a remarkable reduction of HBV infection and production. Based on these novel findings, we hypothesize that apoE is incorporated into HBV virions and plays important roles in HBV infection and morphogenesis in vivo. The overall goal of this application is to determine the role and underlying molecular mechanisms of apoE in the promotion of HBV infection and morphogenesis in cell culture and in vivo. Our specific aims are: 1) to determine the importance of apoE in the infection and morphogenesis of clinical HBV isolates; 2) to determine apoE-binding receptors and apoE-receptor interactions important for efficient HBV infection; and 3) to illustrate the underlying molecular mechanism of apoE-mediated promotion of HBV morphogenesis. The successful completion of this application will result in a paradigm change regarding the roles of cellular proteins in HBV infection and morphogenesis. The outcomes of our studies will also provide novel molecular targets for discovery and development of antiviral drugs towards the ultimate elimination of HBV infection.

总结